Dataset Information

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross.

ABSTRACT: Binge eating is a heritable trait associated with eating disorders and refers to the rapid consumption of a large quantity of energy-dense food that is, associated with loss of control and negative affect. Binge eating disorder is the most common eating disorder in the United States; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge-like eating of sweetened palatable food in an intermittent access, conditioned place preference paradigm. To map the genetic basis of changes in body weight and binge-like eating (BLE) and to identify candidate genes, we conducted quantitative trait locus (QTL) analysis in 128 C57BL/6J x DBA/2J-F2 mice combined with PheQTL and trait covariance analysis in GeneNetwork2 using legacy BXD-RI trait datasets. We identified a QTL on Chromosome 18 influencing changes in body weight across days in females (log of the odds [LOD] = 6.3; 1.5-LOD: 3-12 cM) that contains the candidate gene Zeb1. We also identified a sex-combined QTL influencing initial palatable food intake on Chromosome 5 (LOD = 5.8; 1.5-LOD: 21-28 cM) that contains the candidate gene Lcorl and a second QTL influencing escalated palatable food intake on Chromosome 6 in males (LOD = 5.4; 1.5-LOD: 50-59 cM) that contains the candidate genes Adipor2 and Plxnd1. Finally, we identified a suggestive QTL in females for slope of BLE on distal Chromosome 18 (LOD = 4.1; p = 0.055; 1.5-LOD: 23-35 cM). Future studies will use BXD-RI strains to fine map loci and support candidate gene nomination for gene editing.

SUBMITTER: Yao EJ

PROVIDER: S-EPMC9361732 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross.

Yao Emily J EJ Babbs Richard K RK Kelliher Julia C JC Luttik Kimberly P KP Borrelli Kristyn N KN Damaj M Imad MI Mulligan Megan K MK Bryant Camron D CD

Genes, brain, and behavior 20210512

Binge eating is a heritable trait associated with eating disorders and refers to the rapid consumption of a large quantity of energy-dense food that is, associated with loss of control and negative affect. Binge eating disorder is the most common eating disorder in the United States; however, the genetic basis is unknown. We previously identified robust mouse inbred strain differences between C57BL/6J and DBA/2J in binge-like eating of sweetened palatable food in an intermittent access, conditio ...[more]

PMID: 33978997

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Project description:Prenatal alcohol exposure can result in fetal alcohol spectrum disorders (FASD). Not all women who consume alcohol during pregnancy have children with FASD and studies have shown that genetic factors can play a role in ethanol teratogenesis. We examined gene expression in embryos and placentae from C57BL/6J (B6) and DBA/2J (D2) mice following prenatal alcohol exposure. B6 fetuses are susceptible to morphological malformations following prenatal alcohol exposure while D2 are relatively resistant.Male and female B6 and D2 mice were mated for 2 hours in the morning, producing 4 embryonic genotypes: true-bred B6B6 and D2D2, and reciprocal B6D2 and D2B6. On gestational day 9, dams were intubated with 5.8 g/kg ethanol, an isocaloric amount of maltose dextrin, or nothing. Four hours later, dams were sacrificed and embryos and placentae were harvested. RNA was extracted, labeled and hybridized to Affymetrix Mouse Genome 430 v2 microarray chips. Data were normalized, subjected to analysis of variance and tested for enrichment of gene ontology molecular function and biological process using the Database for Annotation, Visualization and Integrated Discovery (DAVID).Several gene classes were differentially expressed in B6 and D2 regardless of treatment, including genes involved in polysaccharide binding and mitosis. Prenatal alcohol exposure altered expression of a subset of genes, including genes involved in methylation, chromatin remodeling, protein synthesis, and mRNA splicing. Very few genes were differentially expressed between maltose-exposed tissues and tissues that received nothing, so we combined these groups for comparisons with ethanol. While we observed many expression changes specific to B6 following prenatal alcohol exposure, none were specific for D2. Gene classes up- or down-regulated in B6 following prenatal alcohol exposure included genes involved in mRNA splicing, transcription, and translation.Our study identified several classes of genes with altered expression following prenatal alcohol exposure, including many specific for B6, a strain susceptible to ethanol teratogenesis. Lack of strain specific effects in D2 suggests there are few gene expression changes that confer resistance. Future studies will begin to analyze functional significance of the expression changes.

Project description:C57BL/6J (B6) and DBA/2J (D2) are two of the most commonly used inbred mouse strains in neuroscience research. However, the only currently available mouse genome is based entirely on the B6 strain sequence. Subsequently, oligonucleotide microarray probes are based solely on this B6 reference sequence, making their application for gene expression profiling comparisons across mouse strains dubious due to their allelic sequence differences, including single nucleotide polymorphisms (SNPs). The emergence of next-generation sequencing (NGS) and the RNA-Seq application provides a clear alternative to oligonucleotide arrays for detecting differential gene expression without the problems inherent to hybridization-based technologies. Using RNA-Seq, an average of 22 million short sequencing reads were generated per sample for 21 samples (10 B6 and 11 D2), and these reads were aligned to the mouse reference genome, allowing 16,183 Ensembl genes to be queried in striatum for both strains. To determine differential expression, 'digital mRNA counting' is applied based on reads that map to exons. The current study compares RNA-Seq (Illumina GA IIx) with two microarray platforms (Illumina MouseRef-8 v2.0 and Affymetrix MOE 430 2.0) to detect differential striatal gene expression between the B6 and D2 inbred mouse strains. We show that by using stringent data processing requirements differential expression as determined by RNA-Seq is concordant with both the Affymetrix and Illumina platforms in more instances than it is concordant with only a single platform, and that instances of discordance with respect to direction of fold change were rare. Finally, we show that additional information is gained from RNA-Seq compared to hybridization-based techniques as RNA-Seq detects more genes than either microarray platform. The majority of genes differentially expressed in RNA-Seq were only detected as present in RNA-Seq, which is important for studies with smaller effect sizes where the sensitivity of hybridization-based techniques could bias interpretation.

Dataset Information

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross.

Publications

Systems genetic analysis of binge-like eating in a C57BL/6J x DBA/2J-F2 cross.

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